Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury.

Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.

IgA Nephropathy Complicated with X-linked Thrombocytopenia.

Renal involvement is occasionally observed in Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). It has been reported that galactose-deficient IgA is a closely linked to IgA nephropathy (IgAN), suggesting that patients with XLT/WAS associated with reduced galactosylation on serum IgA are susceptible to IgAN. It is necessary to pay more attention to patients with IgAN due to the potential complication with XLT/WAS. We here present a patient of XLT complicated with mild IgAN who underwent tonsillectomy combined with steroid pulse therapy to achieve complete clinical remission.

Resection Arthroplasty Is a Valuable Strategy for Humeroradial Synostosis - A Case Report.

A 15-year-old girl with humeroradial synostosis since birth underwent a resection arthroplasty. A trapezoidal resection osteotomy of approximately 2 cm was performed at the anterior part of the bone flexure. This resulted at 18 months in an elbow arc of motion of 60°-110° and forearm pronation/supination of 40° and 60° without postoperative complications and improved disabilities of the arm, shoulder and hand and Hand 20 scores. Radiographic analysis revealed a humeroradial joint with a maintained pseudarthrosis and hinged motion at the humeroulnar joint. When performed by an experienced surgeon, resection arthroplasty corrects humeroradial synostosis, resulting in improvement in range of motion and quality of life. Level of Evidence: Level V (Therapeutic).

Methylglyoxal inhibition of cytosolic ascorbate peroxidase from Nicotiana tabacum.

Methylglyoxal (MG) is one of the aldehydes accumulated in plants under environmental stress. Cytosolic ascorbate peroxidase (cAPX) plays a key role in the protection of cells from oxidative damage by scavenging reactive oxygen species in higher plants. A cDNA encoding cAPX, named NtcAPX, was isolated from Nicotiana tabacum. We characterized recombinant NtcAPX (rNtcAPX) as a fusion protein with glutathione S-transferase to investigate the effects of MG on APX. NtcAPX consists of 250 amino acids and has a deduced molecular mass of 27.5 kDa. The rNtcAPX showed a higher APX activity. MG treatments resulted in a reduction of APX activity and modifications of amino groups in rNtcAPX with increasing K(m) for ascorbate. On the contrary, neither NaCl nor cadmium reduced the activity of APX. The present study suggests that inhibition of APX is in part due to the modification of amino acids by MG.

Effects of oral administration of Lactobacillus acidophilus L-92 on the symptoms and serum markers of atopic dermatitis in children.

BACKGROUND: Few studies have investigated the complementary effects of long-term oral administration of Lactobacillus acidophilus on traditional medical therapy in the treatment of patients with atopic dermatitis (AD). METHODS: The Atopic Dermatitis Area and Severity Index was used to evaluate AD severity. Symptom severity was assessed using the symptom score. The effect of medical therapy was evaluated by adding the medication score, calculated as the sum of each product of the amount of steroid ointment used for therapy and its designated strength graded on a 4-point scale, to the symptom score. The complementary effect of long-term oral administration of L. acidophilus strain L-92 (L-92) as a probiotic or biogenic strain in patients with AD was evaluated using the symptom-medication score, which was calculated as the sum of the symptom score and medication score. Both a preliminary casuistic study and a double-blinded, placebo-controlled study were performed to evaluate the effects of L-92 on the symptoms of AD in children. RESULTS: Orally administered L-92 significantly ameliorated the symptoms of AD in Japanese children. L-92 also affected the serum concentrations of thymus and activation-regulated chemokine in a time-dependent manner. CONCLUSIONS: The results of the preliminary trial and the double-blinded, placebo-controlled study revealed a complementary effect of oral L-92 on the standard medical therapy (topical application of a steroid ointment) in patients with AD that was mediated, at least in part, by alterations in the Th1/Th2 balance.

The level of urinary semaphorin3A is associated with disease activity in patients with minimal change nephrotic syndrome.

Semaphorin3A is a secreted protein known to be involved in organogenesis, immune responses and cancer. In the kidney, semaphorin3A is expressed in the glomerular podocytes, distal tubules and collecting tubules, and believed to play a role in the regulation of the kidney development and function. We examined the serum and urinary semaphorin3A levels in 72 patients with renal disease and 5 healthy volunteers. The patients had been diagnosed with thin basement membrane disease (n=4), minimal change nephrotic syndrome (MCNS; n=22), IgA nephritis (n=21), membranous nephropathy (n=16) and focal segmental glomerular sclerosis (n=9). The level of urinary semaphorin3A in MCNS patients tended to be relatively high among all disease groups. We also investigated the urinary semaphorin3A level in 7 patients with MCNS from disease onset to remission during the drug therapy. MCNS patients in pre-remission states had higher urinary semaphorin3A levels than those in post-remission states receiving immunosuppressive therapies. These results suggested that the urinary semaphorin3A level correlates with the MCNS activity. Semaphorin3A has the potential as a biomarker for MCNS to clarify the reactivity for therapy and may be useful in examining other glomerular diseases with proteinuria as well.

Vitamin A reduces lung granulomatous inflammation with eosinophilic and neutrophilic infiltration in Sephadex-treated rats.

Vitamin A is known to suppress the activity of the transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), as do glucocorticoids. The possibility that vitamin A exerts various anti-inflammatory effects therefore seems likely. Sephadex beads were administered intravenously to anesthesized rats pretreated with a subcutaneous injection of vitamin A (3000, 10,000, or 30,000 IU/kg) or vehicle once daily for 3 days. After 16 h, the leukocyte differential, tumor necrosis factor (TNF)-alpha and eotaxin, and the DNA-binding activity of NF-kappaB were measured in bronchoalveolar lavage fluid (BALF). Additionally, lung histology was assessed using preparations stained with May-Giemsa stain. Sephadex beads caused histological granulomatous changes and eosinophilic and neutrophilic infiltration into the lung, and markedly increased cell counts of eosinophils and neutrophils, concentrations of TNF-alpha and eotaxin, and NF-kappaB binding to DNA in BALF. Vitamin A significantly inhibited all responses. Vitamin A may inhibit Sephadex-induced lung granulomatous formation, and eosinophilic and neutrophilic infiltration due to its suppression of TNF-alpha and eotaxin production, and NF-kappaB activation.

Lactobacillus Acidophilus strain L-92 regulates the production of Th1 cytokine as well as Th2 cytokines.

BACKGROUND: There is growing interest in probiotics such as lactic acid bacteria (LAB), not only for treatment of T helper type (Th) 1-mediated diseases but also for Th2-mediated diseases, including allergic diseases, since lactic acid bacteria may be able to modulate the Th1/Th2 balance, in addition to having an immunomodulative effect through induction of Th1 bias. METHODS: The effect of oral administration of heat-killed Lactobacillus acidophilus Strain L-92 (L-92) on ovalbumin (OVA)-specific immunoglobulin (Ig)E production was investigated in BALB/c mice. L-92 was orally administered to mice for 8 weeks from 2 weeks after initiation of OVA-immunization. Patterns of cytokine and Ig production in splenocytes and cells from Peyer's patches (PPs) from these mice were examined after restimulation with OVA in vitro. RESULTS: L-92 significantly suppressed serum OVA-specific IgE levels for a long period. Cytokines such as interferon (IFN)-gamma, interleukin (IL)-4 and IL-10 and Igs such as total IgE and OVA-specific IgE were produced at significantly lower levels by splenocytes of L-92-treated mice, compared with those of control mice. In contrast, transforming growth factor (TGF)-beta and IgA levels produced by PPs from L-92-treated mice were significantly higher than in those from control mice. CONCLUSIONS: Oral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-beta production in PPs. TGF-beta is known to be associated with activation of regulatory T (Treg) cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-beta activity.